Perioperative hemorrhage remains a significant concern. Coagulopathy frequently develops in the setting of surgical hemorrhage and the optimal strategy for addressing this issue remains a matter of debate.

Military experience suggests the application of ratio-based plasma transfusion practices may improve clinical outcomes in the setting of massive hemorrhage. However, numerous concerns (e.g. survival bias, uniqueness of a military population, risk for adverse events related to high-volume plasma transfusion) preclude the broad generalization of such strategies to non-trauma surgical populations.

Goal-directed hemostatic resuscitation strategies (e.g. coagulation management based upon the results of hemostasis testing) have shown promise in specific surgical environments such as cardiac surgery and liver transplantation. However, definitive direct comparisons between goal-directed strategies and alternative approaches such as fixed-ratio plasma transfusion have not been performed. Moreover, the role of such strategies in more heterogeneous surgical populations remains uncertain. To better define the optimal approach to plasma transfusion strategies in the setting of intraoperative (non-trauma) hemorrhage, we propose a multicenter clinical trial directly comparing fixed-ratio and goal-directed plasma resuscitation strategies in the operating room environment.

Feasibility and challenges of addressing this CQ or CC:

Surgical patients with increased risk of hemorrhage may be targeted to improve subject recruitment (e.g. cardiac surgery, liver transplantation, aortic vascular surgery, multi-level instrumented spinal fusions or tumor resections, etc). Therefore, an adequately sized study population is likely to be present in a multicenter study and we believe such a trial would be feasible with NHLBI support.

To further enhance the feasibility of identifying a surgical population experiencing significant hemorrhage in a time-efficient manner, predictive algorithms such as the critical RBC administration threshold (CAT) could be also be employed.

The optimization of decisions related to plasma transfusion has the potential to improve not only clinical outcomes, but also healthcare resource utilization. Therefore, the outcomes of a trial in this domain could include both patient-important outcomes (e.g. mortality, bleeding complications), as well as outcomes related to healthcare utilization (e.g. total blood products consumed, hospital length of stay).

Name of idea submitter and other team members who worked on this idea:
Daryl J. Kor, MD and Walter H. Dzik, MD for the 2015 NHLBI State of the Science in Transfusion Medicine.

The PT/INR are frequently used to guide hemostatic interventions, particularly in the ICU where the risk for hemorrhage is increased. In part, this is the result of long standing misconceptions regarding the relationship between PT/INR values with in vivo coagulation factor concentrations and clinical coagulation or hemostasis. Indeed, this misinformation almost certainly contributes to the well-documented inappropriate use of plasma products. To this point, it has now been demonstrated in a variety of clinical settings that the PT/INR is often poorly predictive of clinical coagulopathy or peri-procedural bleeding complications.

The last decade has seen a resurgence of interest in viscoelastic tests as alternatives assessments of hemostasis and guides to blood component use. Indeed, a body of literature supports the potential value of these tests in specific clinical settings. However, the value of such testing strategies has not been well described in the setting of the intensive care unit. Ongoing equipoise regarding the optimal assessment of coagulation status in the ICU suggests that a well conducted trial in this domain would have the potential to be truly transformative.

Feasibility and challenges of addressing this CQ or CC:

The assessment of coagulation status and decisions related to plasma transfusion occurs multiple times throughout the day in essentially every intensive care unit across the US. Therefore, an adequately sized study population is clearly present and therefore, a multicenter trial is feasible with NHLBI support.

A potential challenge with a study evaluating the optimal coagulation testing strategy is the incomplete penetration of viscoelastic testing in current clinical practice raising concerns related to the resource and educational requirements if such a trial were pursued. Additionally, viscoelastic testing can take several forms, each of which may impose specific confounders. Therefore, specific technologies and transfusion algorithms would likely need to be employed.

Importantly, innovative trial designs may also help us to address some of the feasibility concerns noted above. One such design that may prove valuable in this setting is the stepped-wedge cluster randomization design. Implementation of such a design might be expected to improve investigator/clinician cooperation/compliance and may help reduce treatment group contamination.

Name of idea submitter and other team members who worked on this idea:
Daryl J. Kor, MD and Walter H. Dzik, MD for the 2015 NHLBI State of the Science in Transfusion Medicine.

Bleeding is frequently encountered in the ICU and is associated with substantial morbidity and associated mortality. When bleeding occurs, coagulopathy is often present and the optimal coagulation factor management regimen remains a matter of debate. Traditionally (and presently in the US), plasma transfusion has been a cornerstone therapy for the replacement of coagulation factor content in this setting. Moreover, recent evidence supporting the use of plasma in the setting of trauma-related hemorrhage seems to have also generated a renewed enthusiasm for plasma transfusion in other critical care settings.

In many locations, there is interest in alternatives to plasma transfusion such as four-factor prothrombin complex concentrates (PCC4) for ICU patients with bleeding. In some locations, factor concentrates have entirely replaced plasma transfusion. However, evidence regarding the benefits and risks of PCC4 versus plasma in ICU patients is lacking. Therefore, we would aim to study the comparative efficacy and risks of a hemostatic strategy relying on PCC4 versus plasma for ICU patients with coagulopathy and bleeding.

Feasibility and challenges of addressing this CQ or CC:

Coagulopathy and associated bleeding are common in the intensive care unit environment. Therefore, we believe a multicenter clinical trial evaluating the knowledge gap identified above would be feasible with NHLBI support. Of note, due to the labeled contraindication of disseminated intravascular coagulation for PCC4, such patients would need to be excluded from this trial. Similarly, coagulation abnormalities resulting from congenital coagulation factor deficiencies for which there is a specific coagulation factor product available would also be excluded.

Notably, improved management of coagulopathic bleeding has the potential to impact both clinical outcomes and healthcare resource utilization. Therefore, the outcomes of a trial addressing this knowledge gap would include patient-important outcomes (e.g. mortality, length of hospital stay, bleeding, transfusion-related respiratory complications, thromboembolic complications) as well as outcomes related to healthcare utilization (e.g. product cost, total blood products consumed, interventions required to achieve hemostasis such as surgery or embolization).

Name of idea submitter and other team members who worked on this idea:
Daryl J. Kor, MD and Walter H. Dzik, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

Voting

At what INR threshold does prophylactic plasma transfusion, in non-bleeding critically ill patients who are planned to undergo an invasive procedure, prevent bleeding complications and improve patient outcomes?

Millions of plasma units continue to be transfused to non-bleeding critically ill patients. This practice persists despite the lack of high quality evidence indicating improved patient outcomes with prophylactic plasma transfusion triggered by the INR. Studies testing restrictive versus liberal transfusion triggers are now well-established in academic medicine for Red Blood Cell products. More recently, multicenter clinical trials of prophylactic platelet transfusion vs no-prophylaxis have been conducted as well. However, there remains substantial equipoise on the topic of prophylactic plasma transfusion. A large definitive clinical trial that aims to identify the INR threshold at which prophylactic plasma transfusion prevents bleeding complications in non-bleeding critically ill patients would impact clinical practice in a very meaningful way.

Feasibility and challenges of addressing this CQ or CC:

Abnormal coagulation tests are common in the ICU and plasma is frequently administered in this specific clinical setting. Indeed, more plasma is administered in the ICU environment than in any other clinical area. Therefore, a multi-center clinical trial addressing the knowledge gap identified above would be feasible with NHLBI support.

Importantly, healthcare providers become increasingly uncomfortable with the avoidance of coagulation factor replacement as coagulation screening test results drift further from the normal range. To address this concern, an adaptive clinical trial may be desirable. In this design, a targeted cohort with modest elevations in the INR measurement would be screened for enrollment (e.g. INR results ranging from 1.5 - 2.0). If the avoidance of plasma transfusion is noted to be safe, the study would advance to the next stage of recruitment, targeting a higher range of INR values (e.g. 2.0 - 2.5).

Finally, the value of the INR in predicting bleeding complications is increasingly scrutinized. Therefore, it can be argued that the INR is not the ideal "trigger" for plasma transfusion. Despite this, it must be acknowledged that the INR remains the primary driver of decisions related to plasma transfusion. Therefore, a large definitive trial specifically detailing the the efficacy of the current practice versus a more conservative approach to prophylactic plasma transfusion would be practice changing and potentially very transformative.

Name of idea submitter and other team members who worked on this idea:
Daryl J. Kor, MD and Walter H. Dzik, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.